Glutathione S-transferase (GST) family, N-terminal domain; a large, diverse group of cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. In addition, GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. This family, also referred to as soluble GSTs, is the largest family of GSH transferases and is only distantly related to the mitochondrial GSTs (GSTK subfamily, a member of the DsbA family). Soluble GSTs bear no structural similarity to microsomal GSTs (MAPEG family) and display additional activities unique to their group, such as catalyzing thiolysis, reduction and isomerization of certain compounds. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. Based on sequence similarity, different classes of GSTs have been identified, which display varying tissue distribution, substrate specificities and additional specific activities. In humans, GSTs display polymorphisms which may influence individual susceptibility to diseases such as cancer, arthritis, allergy and sclerosis. Some GST family members with non-GST functions include glutaredoxin 2, the CLIC subfamily of anion channels, prion protein Ure2p, crystallins, metaxin 2 and stringent starvation protein A.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 494647661   3 QLYQFPLCPFSRKVRLLLGEKGVGYELVRESPWQRR-DEFLDMNPAGQTPVMVDEerGVLLVDSMAISEFFE 73
Cdd:cd00570    2 KLYYFPGSPRSLRVRLALEEKGLPYELVPVDLGEGEqEEFLALNPLGKVPVLEDG--GLVLTESLAILEYLA 71

putative glutathione S-transferase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 494647661  11 PFSRKVRLLLGEKGVGYELVRESPWQRRDEFLDMNPAGQTPVMVDEErGVLLVDSMAISEFFEETVEKSAMINGTAVGRA 90
Cdd:PRK10357  10 PFVRKISILLLEKGITFEFVNELPYNADNGVAQYNPLGKVPALVTEE-GECWFDSPIIAEYIELLNVAPAMLPRDPLAAL 88

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 494647661  91 EIRRLVTWFDthfyqDVTGPLLheRMVKRVARTGS--PDAKGLREAMKAAVGhLDYTD-YLLDHRnwLGGATMSLADLAA 167
Cdd:PRK10357  89 RVRQLEALAD-----GIMDAAL--VSVREQARPAAqqSEDELLRQREKINRS-LDALEgYLVDGT--LKTDTVNLATIAI 158

                        170
                 ....*....|
gi 494647661 168 AAQISvadYL 177
Cdd:PRK10357 159 ACAVG---YL 165

Glutathione S-transferase (GST) family, N-terminal domain; a large, diverse group of cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. In addition, GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. This family, also referred to as soluble GSTs, is the largest family of GSH transferases and is only distantly related to the mitochondrial GSTs (GSTK subfamily, a member of the DsbA family). Soluble GSTs bear no structural similarity to microsomal GSTs (MAPEG family) and display additional activities unique to their group, such as catalyzing thiolysis, reduction and isomerization of certain compounds. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. Based on sequence similarity, different classes of GSTs have been identified, which display varying tissue distribution, substrate specificities and additional specific activities. In humans, GSTs display polymorphisms which may influence individual susceptibility to diseases such as cancer, arthritis, allergy and sclerosis. Some GST family members with non-GST functions include glutaredoxin 2, the CLIC subfamily of anion channels, prion protein Ure2p, crystallins, metaxin 2 and stringent starvation protein A.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 494647661   3 QLYQFPLCPFSRKVRLLLGEKGVGYELVRESPWQRR-DEFLDMNPAGQTPVMVDEerGVLLVDSMAISEFFE 73
Cdd:cd00570    2 KLYYFPGSPRSLRVRLALEEKGLPYELVPVDLGEGEqEEFLALNPLGKVPVLEDG--GLVLTESLAILEYLA 71

Glutathione S-transferase, N-terminal domain;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 494647661    4 LYQFPLCPFSRKVRLLLGEKGVGYELVRESPWQRRDEFLDMNPAGQTPVMVDEerGVLLVDSMAISEFFEETVE 77
Cdd:pfam13417   1 LYGFPGSPYARRVRIALNEKGLPYEFVPIPPGDHPPELLAKNPLGKVPVLEDD--GGILCESLAIIDYLEELYP 72

GST_N family, Saccharomyces cerevisiae GTT2-like subfamily; composed of predominantly uncharacterized proteins with similarity to the S. cerevisiae GST protein, GTT2. GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. GTT2, a homodimer, exhibits GST activity with standard substrates. Strains with deleted GTT2 genes are viable but exhibit increased sensitivity to heat shock.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 494647661   4 LYQFPLCPFSRKVRLLLGEKGVGYELVRESPW---QRRDEFLDMNPAGQTPVMVDEErGVLLVDSMAISEFFE 73
Cdd:cd03051    3 LYDSPTAPNPRRVRIFLAEKGIDVPLVTVDLAageQRSPEFLAKNPAGTVPVLELDD-GTVITESVAICRYLE 74

GST_N family, unknown subfamily 3; composed of uncharacterized bacterial proteins with similarity to GSTs. GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 494647661   3 QLYQFPLCPFSRKVRLLLGEKGVG--YELVRESPWQRRDEFLDMNPAGQTPVMVDEErGVLLVDSMAISEF 71
Cdd:cd03049    2 KLLYSPTSPYVRKVRVAAHETGLGddVELVLVNPWSDDESLLAVNPLGKIPALVLDD-GEALFDSRVICEY 71

Glutathione S-transferase, N-terminal domain; Function: conjugation of reduced glutathione to a variety of targets. Also included in the alignment, but not GSTs: S-crystallins from squid (similarity to GST previously noted); eukaryotic elongation factors 1-gamma (not known to have GST activity and similarity not previously recognized); HSP26 family of stress-related proteins including auxin-regulated proteins in plants and stringent starvation proteins in E. coli (not known to have GST activity and similarity not previously recognized). The glutathione molecule binds in a cleft between the N- and C-terminal domains - the catalytically important residues are proposed to reside in the N-terminal domain.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 494647661    4 LYQFPLCPFSRKVRLLLGEKGVGYELVRESPW---QRRDEFLDMNPAGQTPVMVDEerGVLLVDSMAISEFFEE 74
Cdd:pfam02798   5 LYGIRGSPRAHRIRWLLAEKGVEYEIVPLDFGagpEKSPELLKLNPLGKVPALEDG--GKKLTESRAILEYIAR 76

GST_N family, Class Phi subfamily; composed of plant-specific class Phi GSTs and related fungal and bacterial proteins. GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. The class Phi GST subfamily has experience extensive gene duplication. The Arabidopsis and Oryza genomes contain 13 and 16 Phi GSTs, respectively. They are primarily responsible for herbicide detoxification together with class Tau GSTs, showing class specificity in substrate preference. Phi enzymes are highly reactive toward chloroacetanilide and thiocarbamate herbicides. Some Phi GSTs have other functions including transport of flavonoid pigments to the vacuole, shoot regeneration and GSH peroxidase activity.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 494647661   4 LYQFPLCPFSRKVRLLLGEKGVGYELVRESPW---QRRDEFLDMNPAGQTPVMVDEerGVLLVDSMAISEFFEE 74
Cdd:cd03053    4 LYGAAMSTCVRRVLLCLEEKGVDYELVPVDLTkgeHKSPEHLARNPFGQIPALEDG--DLKLFESRAITRYLAE 75

GST_N family, 2 repeats of the N-terminal domain of soluble GSTs (2 GST_N) subfamily; composed of uncharacterized proteins. GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins, and products of oxidative stress. GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 494647661   1 MWQLYQFPLCPFSRKVRLLLGEKGVGYELV---RESPwqRRDEFLDMNPAGQTPVMVDEERGVLLVDSMAISEFFEET 75
Cdd:cd03041    1 PLELYEFEGSPFCRLVREVLTELELDVILYpcpKGSP--KRDKFLEKGGKVQVPYLVDPNTGVQMFESADIVKYLFKT 76

glutathione S-transferase

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 494647661   8 PLCPFSRKVRLLLGEKGVGYELVRE---SPWQRRDEFLDMNPAGQTPVMVDEErgVLLVDSMAISEFFEETVEKSA--MI 82
Cdd:PLN02395   8 PAFASPKRALVTLIEKGVEFETVPVdlmKGEHKQPEYLALQPFGVVPVIVDGD--YKIFESRAIMRYYAEKYRSQGpdLL 85

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 494647661  83 NGTAVGRAEIRRlvtWFD---THFYQDVTGPLLHerMVKRVARTGSPDAKGLREAMKAAVGHLDYTDYLLDHRNWLGGAT 159
Cdd:PLN02395  86 GKTIEERGQVEQ---WLDveaTSYHPPLLNLTLH--ILFASKMGFPADEKVIKESEEKLAKVLDVYEARLSKSKYLAGDF 160

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|..
gi 494647661 160 MSLADLaaaAQISVADYLGGIDWKGH-----EQTARWYRGLKSRPSFRPLLS 206
Cdd:PLN02395 161 VSLADL---AHLPFTEYLVGPIGKAYlikdrKHVSAWWDDISSRPAWKEVLA 209

GST_N family, Class Zeta subfamily; GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. Class Zeta GSTs, also known as maleylacetoacetate (MAA) isomerases, catalyze the isomerization of MAA to fumarylacetoacetate, the penultimate step in tyrosine/phenylalanine catabolism, using GSH as a cofactor. They show little GSH-conjugating activity towards traditional GST substrates but display modest GSH peroxidase activity. They are also implicated in the detoxification of the carcinogen dichloroacetic acid by catalyzing its dechlorination to glyoxylic acid.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 494647661  13 SRKVRLLLGEKGVGYE-----LVRESpwQRRDEFLDMNPAGQTPVMVDEerGVLLVDSMAISEFFE 73
Cdd:cd03042   12 SYRVRIALNLKGLDYEyvpvnLLKGE--QLSPAYRALNPQGLVPTLVID--GLVLTQSLAIIEYLD 73

GST_N family, Class Omega subfamily; GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. Class Omega GSTs show little or no GSH-conjugating activity towards standard GST substrates. Instead, they catalyze the GSH dependent reduction of protein disulfides, dehydroascorbate and monomethylarsonate, activities which are more characteristic of glutaredoxins. They contain a conserved cysteine equivalent to the first cysteine in the CXXC motif of glutaredoxins, which is a redox active residue capable of reducing GSH mixed disulfides in a monothiol mechanism. Polymorphisms of the class Omega GST genes may be associated with the development of some types of cancer and the age-at-onset of both Alzheimer's and Parkinson's diseases.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 494647661   4 LYQFPLCPFSRKVRLLLGEKGVGYELVRESPWQRRDEFLDMNPAGQTPVmVDEERGVLLVDSMAISEF 71
Cdd:cd03055   21 LYSMRFCPYAQRARLVLAAKNIPHEVININLKDKPDWFLEKNPQGKVPA-LEIDEGKVVYESLIICEY 87

GST_N family, Class Delta and Epsilon subfamily; GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. The class Delta and Epsilon subfamily is made up primarily of insect GSTs, which play major roles in insecticide resistance by facilitating reductive dehydrochlorination of insecticides or conjugating them with GSH to produce water-soluble metabolites that are easily excreted. They are also implicated in protection against cellular damage by oxidative stress.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 494647661   4 LYQFPLCPFSRKVRLLLGEKGVGYELVRESPW---QRRDEFLDMNPAGQTPVMVDEerGVLLVDSMAI 68
Cdd:cd03045    3 LYYLPGSPPCRAVLLTAKALGLELNLKEVNLMkgeHLKPEFLKLNPQHTVPTLVDN--GFVLWESHAI 68

GST_N family; microsomal Prostaglandin E synthase Type 2 (mPGES2) subfamily; mPGES2 is a membrane-anchored dimeric protein containing a CXXC motif which catalyzes the isomerization of PGH2 to PGE2. Unlike cytosolic PGE synthase (cPGES) and microsomal PGES Type 1 (mPGES1), mPGES2 does not require glutathione (GSH) for its activity, although its catalytic rate is increased two- to four-fold in the presence of DTT, GSH or other thiol compounds. PGE2 is widely distributed in various tissues and is implicated in the sleep/wake cycle, relaxation/contraction of smooth muscle, excretion of sodium ions, maintenance of body temperature and mediation of inflammation. mPGES2 contains an N-terminal hydrophobic domain which is membrane associated, and a C-terminal soluble domain with a GST-like structure.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 494647661   3 QLYQFPLCPFSRKVRLLLGEKGVGYELVRESPWQRRDefLDMNPAGQTP-VMVD-EERGVLLVDSMAI 68
Cdd:cd03040    3 TLYQYKTCPFCCKVRAFLDYHGIPYEVVEVNPVSRKE--IKWSSYKKVPiLRVEsGGDGQQLVDSSVI 68

C-terminal, alpha helical domain of Class Delta and Epsilon Glutathione S-transferases; Glutathione S-transferase (GST) C-terminal domain family, Class Delta and Epsilon subfamily; GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. The GST fold contains an N-terminal thioredoxin-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. GSH binds to the N-terminal domain while the hydrophobic substrate occupies a pocket in the C-terminal domain. The class Delta and Epsilon subfamily is made up primarily of insect GSTs, which play major roles in insecticide resistance by facilitating reductive dehydrochlorination of insecticides or conjugating them with GSH to produce water-soluble metabolites that are easily excreted. They are also implicated in protection against cellular damage by oxidative stress.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 494647661  89 RAEI-RRLvtWFDT-HFYQ---DVTGPLLhermvkrvaRTGSPDAKGLREAMKAAVGHLDYtdyLLDHRNWLGGATMSLA 163
Cdd:cd03177    3 RAIVnQRL--FFDSgTLYQrlrDYYYPIL---------FGGAEPPEEKLDKLEEALEFLET---FLEGSDYVAGDQLTIA 68

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 494647661 164 DLAAAAQISVADYLgGIDWKGHEQTARWYRGLKSRPSFRPLLSERMEM 211
Cdd:cd03177   69 DLSLVATVSTLEVV-GFDLSKYPNVAAWYERLKALPPGEEENGEGAKE 115

glutathione S-transferase DHAR1

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 494647661  10 CPFSRKVRLLLGEKGVGYELVRESPWQRRDEFLDMNPAGQTPVMVDEERGVllVDSMAISEFFEE 74
Cdd:PLN02378  20 CPFSQRALLTLEEKSLTYKIHLINLSDKPQWFLDISPQGKVPVLKIDDKWV--TDSDVIVGILEE 82

GST_N family, Glutaredoxin 2 (GRX2) subfamily; composed of bacterial proteins similar to E. coli GRX2, an atypical GRX with a molecular mass of about 24kD, compared with other GRXs which are 9-12kD in size. GRX2 adopts a GST fold containing an N-terminal thioredoxin-fold domain and a C-terminal alpha helical domain. It contains a redox active CXXC motif located in the N-terminal domain but is not able to reduce ribonucleotide reductase like other GRXs. However, it catalyzes GSH-dependent protein disulfide reduction of other substrates efficiently. GRX2 is thought to function primarily in catalyzing the reversible glutathionylation of proteins in cellular redox regulation including stress responses.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 494647661   3 QLYQFPLCPFSRKVRLLLGEKGVGYELVresPWQRRDE--FLDMNPAGQTPVMvDEERGVLLVDSMAISEFFEE 74
Cdd:cd03037    2 KLYIYEHCPFCVKARMIAGLKNIPVEQI---ILQNDDEatPIRMIGAKQVPIL-EKDDGSFMAESLDIVAFIDE 71

C-terminal, alpha helical domain of Ure2p and related Glutathione S-transferase-like proteins; Glutathione S-transferase (GST) C-terminal domain family, Ure2p-like subfamily; composed of the Saccharomyces cerevisiae Ure2p, YfcG and YghU from Escherichia coli, and related GST-like proteins. Ure2p is a regulator for nitrogen catabolism in yeast. It represses the expression of several gene products involved in the use of poor nitrogen sources when rich sources are available. A transmissible conformational change of Ure2p results in a prion called [Ure3], an inactive, self-propagating and infectious amyloid. Ure2p displays a GST fold containing an N-terminal thioredoxin-fold domain and a C-terminal alpha helical domain. The N-terminal thioredoxin-fold domain is sufficient to induce the [Ure3] phenotype and is also called the prion domain of Ure2p. In addition to its role in nitrogen regulation, Ure2p confers protection to cells against heavy metal ion and oxidant toxicity, and shows glutathione (GSH) peroxidase activity. YfcG and YghU are two of the nine GST homologs in the genome of Escherichia coli. They display very low or no GSH transferase, but show very good disulfide bond oxidoreductase activity. YghU also shows modest organic hydroperoxide reductase activity. GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of GSH with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. The GST active site is located in a cleft between the N- and C-terminal domains. GSH binds to the N-terminal domain while the hydrophobic substrate occupies a pocket in the C-terminal domain.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 494647661 146 DYLLDHRNWLGGATMSLADLAAAAQISVADYLGGIDWKGHEQTARWYRGLKSRPSFRP 203
Cdd:cd03178   53 DKRLSDRPYLAGEEYSIADIALYPWTHYADLGGFADLSEYPNVKRWLERIAARPAVQK 110